Overview of global real-world data sources for pediatric pharmacoepidemiologic research.

PURPOSE: Given limited information available on real-world data (RWD) sources with pediatric populations, this study describes features of globally available RWD sources for pediatric pharmacoepidemiologic research. METHODS: An online questionnaire about pediatric RWD sources and their attributes and capabilities was completed by members and affiliates of the International Society for Pharmacoepidemiology and representatives of nominated databases. All responses were verified by database representatives and summarized. RESULTS: Of 93 RWD sources identified, 55 unique pediatric RWD sources were verified, including data from Europe (47%), United States (38%), multiregion (7%), Asia-Pacific (5%), and South America (2%). Most databases had nationwide coverage (82%), contained electronic health/medical records (47%) and/or administrative claims data (42%) and were linkable to other databases (65%). Most (71%) had limited outside access (e.g., by approval or through local collaborators); only 10 (18%) databases were publicly available. Six databases (11%) reported having >20 million pediatric observations. Most (91%) included children of all ages (birth until 18th birthday) and contained outpatient medication data (93%), while half (49%) contained inpatient medication data. Many databases captured vaccine information for children (71%), and one-third had regularly updated data on pediatric height (31%) and weight (33%). Other pediatric data attributes captured include diagnoses and comorbidities (89%), lab results (58%), vital signs (55%), devices (55%), imaging results (42%), narrative patient histories (35%), and genetic/biomarker data (22%). CONCLUSIONS: This study provides an overview with key details about diverse databases that allow researchers to identify fit-for-purpose RWD sources suitable for pediatric pharmacoepidemiologic research.

A CRISPR toolbox for generating intersectional genetic mouse models for functional, molecular, and anatomical circuit mapping.

BACKGROUND: The functional understanding of genetic interaction networks and cellular mechanisms governing health and disease requires the dissection, and multifaceted study, of discrete cell subtypes in developing and adult animal models. Recombinase-driven expression of transgenic effector alleles represents a significant and powerful approach to delineate cell populations for functional, molecular, and anatomical studies. In addition to single recombinase systems, the expression of two recombinases in distinct, but partially overlapping, populations allows for more defined target expression. Although the application of this method is becoming increasingly popular, its experimental implementation has been broadly restricted to manipulations of a limited set of common alleles that are often commercially produced at great expense, with costs and technical challenges associated with production of intersectional mouse lines hindering customized approaches to many researchers. Here, we present a simplified CRISPR toolkit for rapid, inexpensive, and facile intersectional allele production. RESULTS: Briefly, we produced 7 intersectional mouse lines using a dual recombinase system, one mouse line with a single recombinase system, and three embryonic stem (ES) cell lines that are designed to study the way functional, molecular, and anatomical features relate to each other in building circuits that underlie physiology and behavior. As a proof-of-principle, we applied three of these lines to different neuronal populations for anatomical mapping and functional in vivo investigation of respiratory control. We also generated a mouse line with a single recombinase-responsive allele that controls the expression of the calcium sensor Twitch-2B. This mouse line was applied globally to study the effects of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) on calcium release in the ovarian follicle. CONCLUSIONS: The lines presented here are representative examples of outcomes possible with the successful application of our genetic toolkit for the facile development of diverse, modifiable animal models. This toolkit will allow labs to create single or dual recombinase effector lines easily for any cell population or subpopulation of interest when paired with the appropriate Cre and FLP recombinase mouse lines or viral vectors. We have made our tools and derivative intersectional mouse and ES cell lines openly available for non-commercial use through publicly curated repositories for plasmid DNA, ES cells, and transgenic mouse lines.

Use of Linked Databases for Improved Confounding Control: Considerations for Potential Selection Bias.

Pharmacoepidemiologic studies are increasingly conducted within linked databases, often to obtain richer confounder data. However, the potential for selection bias is frequently overlooked when linked data is available only for a subset of patients. We highlight the importance of accounting for potential selection bias by evaluating the association between antipsychotics and type 2 diabetes in youths within a claims database linked to a smaller laboratory database. We used inverse probability of treatment weights (IPTW) to control for confounding. In analyses restricted to the linked cohorts, we applied inverse probability of selection weights (IPSW) to create a population representative of the full cohort. We used pooled logistic regression weighted by IPTW only or IPTW and IPSW to estimate treatment effects. Metabolic conditions were more prevalent in linked cohorts compared with the full cohort. Within the full cohort, the confounding-adjusted hazard ratio was 2.26 (95% CI: 2.07, 2.49) comparing initiation of antipsychotics with initiation of control medications. Within the linked cohorts, a different magnitude of association was obtained without adjustment for selection, whereas applying IPSW resulted in point estimates similar to the full cohort's (e.g., an adjusted hazard ratio of 1.63 became 2.12). Linked database studies may generate biased estimates without proper adjustment for potential selection bias.

Development and Validation of a Pediatric Comorbidity Index.

Comorbidity scores are widely used to help address confounding bias in nonrandomized studies conducted within health-care databases, but existing scores were developed to predict all-cause mortality in adults and might not be appropriate for use in pediatric studies. We developed and validated a pediatric comorbidity index, using health-care utilization data from the tenth revision of the International Classification of Diseases. Within the MarketScan database of US commercial claims data, pediatric patients (aged ≤18 years) continuously enrolled between October 1, 2015, and September 30, 2017, were identified. Logistic regression was used to predict the 1-year risk of hospitalization based on 27 predefined conditions and empirically identified conditions derived from the most prevalent diagnoses among patients with the outcome. A single numerical index was created by assigning weights to each condition based on its ß coefficient. We conducted internal validation of the index and compared its performance with existing adult scores. The pediatric comorbidity index consisted of 24 conditions and achieved a C statistic of 0.718 (95% confidence interval (CI): 0.714, 0.723). The index outperformed existing adult scores in a pediatric population (C statistics ranging from 0.522 to 0.640). The pediatric comorbidity index provides a summary measure of disease burden and can be used for risk adjustment in epidemiologic studies of pediatric patients.

Antidiabetic medication use in commercially insured children and adolescents in the United States from 2004 to 2019.

AIM: To describe the patterns of non-insulin antidiabetic medication use, initiation and adherence in the paediatric population. METHODS: We conducted a descriptive study of non-insulin antidiabetic medication use in children and adolescents (aged 10-18 years) using real-world data from a nationwide US commercial claims database (January 2004-September 2019). Trends in the prevalence of non-insulin antidiabetic medication use overall and by class were evaluated. Among new users of non-insulin antidiabetic agents, medication adherence was examined using group-based trajectory models. RESULTS: In a cohort of more than 1 million paediatric patients, the prevalence of any non-insulin antidiabetic medication use was 75.7 per 100 000 patients in 2004 and more than doubled to 162.0 per 100 000 in 2019. Biguanides (metformin) was by far the most widely used medication class. The use of newer classes was low (<10 per 100 000), but there was an uptake in the use of glucagon-like peptide-1 receptor agonists after liraglutide received paediatric approval in 2019. Medication adherence was poor during the 18 months after treatment initiation: 79.6% of initiators experienced an early treatment interruption (median time to interruption: 90 days among metformin monotherapy initiators) and 21% of initiators did not return for a prescription refill after the first month. CONCLUSIONS: There was a substantial increase in non-insulin antidiabetic medication use among commercially insured paediatric patients from 2004 to 2019. Nearly all patients were treated with metformin, while the use of newer agents remained low. Despite the increase in medication use, short treatment episodes were observed, even among patients with a diagnosis of type 2 diabetes, raising concern over poor adherence.

Assessing the impact of the new ICD-10-CM coding system on pharmacoepidemiologic studies-An application to the known association between angiotensin-converting enzyme inhibitors and angioedema.

PURPOSE: To replicate the well-established association between angiotensin-converting enzyme inhibitors versus beta blockers and angioedema in the International Classification of Diseases, 10th Revision, Clinical Modification (ICD-10-CM) era. METHODS: We conducted a retrospective, inception cohort study in a large insurance database formatted to the Sentinel Common Data Model. We defined study periods spanning the ICD-9-CM era only, ICD-10-CM era only, and ICD-9-CM and ICD-10-CM era and conducted simple-forward mapping (SFM), simple-backward mapping (SBM), and forward-backward mapping (FBM) referencing the General Equivalence Mappings to translate the outcome (angioedema) and covariates from ICD-9-CM to ICD-10-CM. We performed propensity score (PS)-matched and PS-stratified Cox proportional hazards regression to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). RESULTS: In the ICD-9-CM and ICD-10-CM eras spanning April 1 to September 30 of 2015 and 2016, there were 152 017 and 145 232 angiotensin-converting enzyme inhibitor initiators and 115 073 and 116 652 beta-blocker initiators, respectively. The PS-matched HR was 4.19 (95% CI, 2.82-6.23) in the ICD-9-CM era, 4.37 (2.92-6.52) in the ICD-10-CM era using SFM, and 4.64 (3.05-7.07) in the ICD-10-CM era using SBM and FBM. The PS-matched HRs from the mixed ICD-9-CM and ICD-10-CM eras ranged from 3.91 (2.69-5.68) to 4.35 (3.33-5.70). CONCLUSION: The adjusted HRs across different diagnostic coding eras and the use of SFM versus SBM and FBM produced numerically different but clinically similar results. Additional investigations as ICD-10-CM data accumulate are warranted.

Adaptation and Validation of the Combined Comorbidity Score for ICD-10-CM.

BACKGROUND: The combined comorbidity score, which merges the Charlson and Elixhauser comorbidity indices, uses the ninth revision of the International Classification of Diseases, Clinical Modification (ICD-9-CM). In October 2015, the United States adopted the 10th revision (ICD-10-CM). OBJECTIVE: The objective of this study is to examine different coding algorithms for the ICD-10-CM combined comorbidity score and compare their performance to the original ICD-9-CM score. METHODS: Four ICD-10-CM coding algorithms were defined: 2 using General Equivalence Mappings (GEMs), one based on ICD-10-CA (Canadian modification) codes for Charlson and Elixhauser measures, and one including codes from all 3 algorithms. We used claims data from the Clinfomatics Data Mart to identify 2 cohorts. The ICD-10-CM cohort comprised patients who had a hospitalization between January 1, 2016 and March 1, 2016. The ICD-9-CM cohort comprised patients who had a hospitalization between January 1, 2015 and March 1, 2015. We used logistic regression models to predict 30-day hospital readmission for the original score in the ICD-9-CM cohort and for each ICD-10-CM algorithm in the ICD-10-CM cohort. RESULTS: Distributions of each version of the score were similar. The algorithm based on ICD-10-CA codes [c-statistic, 0.646; 95% confidence interval (CI), 0.640-0.653] had the most similar discrimination for readmission to the ICD-9-CM version (c, 0.646; 95% CI, 0.639-0.653), but combining all identified ICD-10-CM codes had the highest c-statistic (c, 0.651; 95% CI, 0.644-0.657). CONCLUSIONS: We propose an ICD-10-CM version of the combined comorbidity score that includes codes identified by ICD-10-CA and GEMs. Compared with the original score, it has similar performance in predicting readmission in a population of United States commercially insured individuals.

Analytical Characterization of an Oil-in-Water Adjuvant Emulsion.

Adjuvants are typically used in subunit vaccine formulations to enhance immune responses elicited by individual antigens. Physical chemical characterization of novel adjuvants is an important step in ensuring their effective use in vaccine formulations. This paper reports application of a panel of quantitative assays developed to analyze and characterize an oil-in-water adjuvant emulsion, which contains glucopyranosyl lipid A (GLA) and is a squalene-based emulsion. GLA is a fully synthetic analogue of monophosphoryl lipid A, which is a Toll-like receptor type 4 agonist and an FDA-approved adjuvant. The GLA-stable emulsion (GLA-SE) is currently being used for a respiratory syncytial virus vaccine in a phase 2 clinical trial. GLA was quantitated using reverse-phased high-performance liquid chromatography (RP-HPLC) coupled to a mass spectrometric detector, achieving higher assay sensitivity than the charged aerosol detection routinely used. Quantitation of the excipients of GLA-SE, including squalene, egg phosphatidyl choline, and Poloxamer 188, was achieved using a simple and rapid RP-HPLC method with evaporative light scattering detection, eliminating chemical derivatization typically required for these chromophore-lacking compounds. DL-α-tocopherol, the antioxidant of the GLA-SE, was quantitated using a RP-HPLC method with conventional UV detection. The experimental results compared well with values expected for these compounds based on targeted composition of the adjuvant. The assays were applied to identify degradation of individual components in a GLA-SE sample that degraded into distinct aqueous and oil phases. The methods developed and reported here are effective tools in monitoring physicochemical integrity of the adjuvant, as well as in formulation studies.

A study on the AMACR catalysed elimination reaction and its application to inhibitor testing.

α-Methylacyl-CoA racemase (AMACR; P504S) catalyses a key step in the degradation of branched-chain fatty acids and is important for the pharmacological activation of Ibuprofen and related drugs. Levels of AMACR are increased in prostate and other cancers, and it is a drug target. Development of AMACR as a drug target is hampered by lack of a convenient assay. AMACR irreversibly catalyses the elimination of HF from 3-fluoro-2-methylacyl-CoA substrates, and this reaction was investigated for use as an assay. Several known inhibitors and alternative substrates reduced conversion of 3-fluoro-2-methyldecanoyl-CoA by AMACR, as determined by (1)H NMR. The greatest reduction of activity was observed with known potent inhibitors. A series of novel acyl-CoA esters with aromatic side chains were synthesised for testing as chromophoric substrates. These acyl-CoA esters were converted to unsaturated products by AMACR, but their use was limited by non-enzymatic elimination. Fluoride sensors were also investigated as a method of quantifying released fluoride and thus AMACR activity. These sensors generally suffered from high background signal and lacked reproducibility under the assay conditions. In summary, the elimination reaction can be used to characterise inhibitors, but it was not possible to develop a convenient colorimetric or fluorescent assay using 3-fluoro-2-methylacyl-CoA substrates.

Risk factors for young-onset invasive and in situ breast cancer.

PURPOSE: Young-onset breast cancers tend to be more aggressive than later-onset tumors and may have different risk factor profiles. Among young-onset cases, there may also be etiologic differences between ductal carcinomas in situ (DCIS) and invasive breast cancer, particularly if some factors promote malignant transformation. METHODS: We evaluated the association between several potential risk factors and young-onset breast cancer in the Two Sister Study (2008-2010), a sister-matched case-control study involving 1,406 women diagnosed with breast cancer before age 50 (1,185 invasive, 221 DCIS) and 1,648 controls. RESULTS: Older age at menarche, younger age at menopause, premenopausal hysterectomy, early age at first-term pregnancy, obesity, and consumption of alcohol were associated with reduced risk of young-onset breast cancer. These patterns remained when we limited analysis to invasive breast cancers. In general, effect estimates were similar for young-onset invasive breast cancer and DCIS, although the number of DCIS cases was small. CONCLUSIONS: In this sister-matched case-control study of young-onset breast cancer, many of the studied risk factors were associated with young-onset invasive breast cancer. There were few discernable differences in risk factors for young-onset DCIS versus young-onset invasive breast cancer.

Low serum magnesium and the development of atrial fibrillation in the community: the Framingham Heart Study.

BACKGROUND: Low serum magnesium has been linked to increased risk of atrial fibrillation (AF) after cardiac surgery. It is unknown whether hypomagnesemia predisposes to AF in the community. METHODS AND RESULTS: We studied 3530 participants (mean age, 44 years; 52% women) from the Framingham Offspring Study who attended a routine examination and were free of AF and cardiovascular disease. We used Cox proportional hazard regression analysis to examine the association between serum magnesium at baseline and risk of incident AF. Analyses were adjusted for conventional AF risk factors, use of antihypertensive medications, and serum potassium. During up to 20 years of follow-up, 228 participants developed AF. Mean serum magnesium was 1.88 mg/dL. The age- and sex-adjusted incidence rate of AF was 9.4 per 1000 person-years (95% confidence interval, 6.7-11.9) in the lowest quartile of serum magnesium (≤1.77 mg/dL) compared with 6.3 per 1000 person-years (95% confidence interval, 4.1-8.4) in the highest quartile (≥1.99 mg/dL). In multivariable-adjusted models, individuals in the lowest quartile of serum magnesium were ~50% more likely to develop AF (adjusted hazard ratio, 1.52; 95% confidence interval, 1.00-2.31; P=0.05) compared with those in the upper quartiles. Results were similar after the exclusion of individuals on diuretics. CONCLUSIONS: Low serum magnesium is moderately associated with the development of AF in individuals without cardiovascular disease. Because hypomagnesemia is common in the general population, a link with AF may have potential clinical implications. Further studies are warranted to confirm our findings and to elucidate the underlying mechanisms.

Geographic Trends in Pediatric Psychotropic Medication Dispensing Before and After the Start of the COVID-19 Pandemic.

OBJECTIVE: This study examined trends and geographic variability in dispensing of prescription psychotropic medications to U.S. youths before and after the start of the COVID-19 pandemic. METHODS: Using national data on prescription medication dispensing, the authors performed a cross-sectional study examining the monthly percent change in psychotropic medications dispensed (total N=95,639,975) to youths (ages 5-18 years) in 2020 versus 2019, across medication classes and geographic regions. RESULTS: For many medications, more were dispensed in March 2020 than in March 2019 and fewer in April-May 2020 versus April-May 2019. Stimulants had the largest decline: -26.4% in May 2020 versus May 2019. The magnitude of the monthly percent change varied by region. CONCLUSIONS: Fewer psychotropic medications were dispensed to U.S. youths after the start of the COVID-19 pandemic compared with 2019. Although some medication classes rebounded to prepandemic dispensing levels by September 2020, dispensing varied by class and region.

Clinical Characterization of Pediatric Erythromelalgia: A Single-Center Case Series.

Erythromelalgia is a descriptive term for severe burning pain and erythema in the distal extremities relieved by cold and exacerbated by heat. Pediatric case series to date are relatively small. We extracted and analyzed medical record data for 42 pediatric patients to describe clinical characteristics, associated conditions, and responses to treatments. Informed consent was obtained according to an IRB-approved protocol that included gene discovery. Three patients had confirmed Nav1.7 sodium channelopathies, with six additional patients under investigation with novel gene candidates. There was a female predominance (2.5:1), and the median onset age was 12 years (IQR = 3-14). Patients saw a median of three specialists (IQR = 2-3) for a diagnosis. The majority (90%) reported bilateral symptoms. Cooling methods usually provided partial relief, while heat and exercise exacerbated pain. No medication appeared to be consistently effective; commonly prescribed medications included sodium channel blockers (n = 37), topical analgesics (n = 26), gabapentin (n = 22), and aspirin (n = 15). Based on the currently published literature, we believe this cohort is the largest pediatric study of erythromelalgia to date. Many findings are consistent with those of previously published case series. Work is in progress to establish a prospective cohort and multi-center registry.

Plasma resistin, adiponectin, and risk of incident atrial fibrillation: the Framingham Offspring Study.

BACKGROUND: We sought to investigate whether higher concentrations of resistin and lower concentrations of adiponectin relate to incident atrial fibrillation (AF) and whether this association is mediated by AF risk factors and inflammation. Resistin and adiponectin are adipokines that have been associated with multiple known risk factors for AF including diabetes, obesity, inflammation, and heart failure. METHODS: We studied the relations between circulating concentrations of both adipokines and incident AF in participants of the Framingham Offspring Study. RESULTS: Participants (n = 2,487) had a mean age of 61 ± 10 years, and 54% were women. During a mean follow-up of 7.6 ± 2.0 years, 206 (8.3%) individuals (96 women) developed incident AF. Plasma resistin concentration was significantly associated with incident AF (multivariable-adjusted hazard ratio [HR] 1.17 per SD [0.41 ng/mL] of natural logarithmically transformed resistin, 95% CI 1.02-1.34, P = .028). The resistin-AF association was attenuated after further adjustment for C-reactive protein (HR per SD increase resistin 1.14, 95% CI 0.99-1.31, P = .073). Adiponectin concentrations were not significantly associated with incident AF (multivariable-adjusted HR of 0.95 per SD [0.62 µg/mL] of logarithmically transformed adiponectin, 95% CI 0.81-1.10, P = .478). CONCLUSION: In our community-based longitudinal study, higher mean concentrations of resistin were associated with incident AF, but the relation was attenuated by adjustment for C-reactive protein. We did not detect a statistically significant association between adiponectin and incident AF. Additional studies are needed to clarify the potential role of adipokines in AF and mechanisms linking adiposity to AF.

A memory-reframing intervention to reduce pain in youth undergoing major surgery: Pilot randomized controlled trial of feasibility and acceptability.

Background: Three to 22% of youth undergoing surgery develop chronic postsurgical pain (CPSP). Negative biases in pain memories (i.e., recalling higher levels of pain as compared to initial reports) are a risk factor for CPSP development. Children's memories for pain are modifiable. Existing memory-reframing interventions reduced negatively biased memories associated with procedural pain and pain after minor surgery. However, not one study has tested the feasibility and acceptability of the memory-reframing intervention in youth undergoing major surgery. Aims: The current pilot randomized clinical trial (RCT; NCT03110367; clinicaltrials.gov) examined the feasibility and acceptability of, as well as adherence to, a memory reframing intervention. Methods: Youth undergoing a major surgery reported their baseline and postsurgery pain levels. Four weeks postsurgery, youth and one of their parents were randomized to receive control or memory-reframing instructions. Following the instructions, parents and youth reminisced about the surgery either as they normally would (control) or using the memory-reframing strategies (intervention). Six weeks postsurgery, youth completed a pain memory interview; parents reported intervention acceptability. Four months postsurgery, youth reported their pain. Results: Seventeen youth (76% girls, Mage = 14.1 years) completed the study. The intervention was feasible and acceptable. Parents, but not youth, adhered to the intervention principles. The effect sizes of the intervention on youth pain memories (ηp 2 = 0.22) and pain outcomes (ηp 2 = 0.23) were used to inform a larger RCT sample size. Conclusions: Memory reframing is a promising avenue in pediatric pain research. Larger RCTs are needed to determine intervention efficacy to improve pain outcomes.

Contexte: Trois à 22 % des jeunes qui subissent une chirurgie développent une douleur post-chirurgicale chronique. Les biais négatifs dans les souvenirs de douleur (c.-à-d., se rappeler de niveaux de douleur plus élevés comparativement aux niveaux initialement rapportés) sont un facteur de risque pour le développement de la douleur post-chirurgicale chronique. Les souvenirs qu'ont les jeunes de la douleur sont modifiables. Les interventions de recadrage des souvenirs existantes ont réduit les souvenirs polarisés négativement qui sont associés à la douleur procédurale et à la douleur aprés une intervention chirurgicale mineure. Cependant, aucune étude n'a testé la faisabilité et l'acceptabilité de l'intervention de recadrage des souvenirs chez les jeunes subissant une intervention chirurgicale majeure.Buts: L'essai clinique randomisé pilote actuel (RCT; NCT03110367; clinicaltrials.gov) a examiné la faisabilité et l'acceptabilité d'une intervention de recadrage des souvenirs, ainsi que l'observance de celle-ci.Méthodes: Des jeunes subissant une intervention chirurgicale majeure ont rapporté leur niveau de douleur initial et post-chirurgical. Quatre semaines aprés la chirurgie, les jeunes et l'un de leurs parents ont été randomisés pour recevoir des instructions de contrôle ou de recadrage des souvenirs. En suivant les instructions, les parents et les jeunes se sont rappelé la chirurgie comme ils le feraient normalement (contrôle) ou en utilisant les stratégies de recadrage des souvenirs (intervention). Six semaines aprés la chirurgie, les jeunes ont été interviewés sur leurs souvenirs de la douleur; les parents ont rapporté l'acceptabilité de l'intervention. Quatre mois aprés la chirurgie, les jeunes ont rapporté leur douleur.Résultats: Dix-sept jeunes (76 % de filles, Mâge = 14,1 ans) ont terminé l'étude. L'intervention s'est révélée faisable et acceptable. Les parents, mais pas les jeunes, ont observé les principes de l'intervention. L'ampleur des effets de l'intervention sur les souvenirs de douleur des jeunes (ηp2 = 0,22) et les résultats de douleur (ηp2 = 0,23) ont été utilisés pour déterminer une taille d'échantillon d'essai contrôlé randomisé plus grande.Conclusions: Le recadrage de la mémoire est une voie prometteuse dans la recherche sur la douleur pédiatrique. Des essais contrôlés randomisés de plus grande taille sont nécessaires pour déterminer l'efficacité de l'intervention pour améliorer les résultats de la douleur.

Comparison of Rates of Type 2 Diabetes in Adults and Children Treated With Anticonvulsant Mood Stabilizers.

Importance: Anticonvulsant mood stabilizer treatment is associated with an increased risk of weight gain, but little is known about the risk of developing type 2 diabetes (T2D). Objective: To evaluate the comparative safety of anticonvulsant mood stabilizers on risk of T2D in adults and children by emulating a target trial. Design, Setting, and Participants: This observational cohort study used data from IBM MarketScan (2010-2019), with a 5-year follow-up period. The nationwide sample of US commercially insured patients included children (aged 10-19 years) and adults (aged 20-65 years) who initiated anticonvulsant mood stabilizer treatment. Data were analyzed from August 2020 to May 2021. Exposures: Initiation and continuation of carbamazepine, lamotrigine, oxcarbazepine, or valproate. Main Outcomes and Measures: Onset of T2D during follow-up. Weighted pooled logistic regression was used to estimate the association of initiation and continuation of carbamazepine, lamotrigine, oxcarbazepine, or valproate with the risk of developing T2D. Inverse probability weights were used to control for confounding and loss to follow-up by measured baseline and time-varying covariates. Results: The analysis included 274 206 adults (159 428 women [58%]; mean [SD] age, 39.9 [13.2] years) and 74 005 children (38 672 girls [52%]; mean [SD] age, 15.6 [2.6] years) who initiated an anticonvulsant mood stabilizer. In adults, initiation of valproate was associated with an increased risk of developing T2D compared with initiation of lamotrigine (5-year risk difference [RD], 1.17%; 95% CI, 0.66% to 1.76%). The number needed to harm was 87 patients initiating valproate for 1 patient to develop T2D within 5 years compared with initiation of lamotrigine. Point estimates were similar when evaluating the association of treatment continuation (5-year RD, 1.99%; 95% CI, -0.64% to 5.31%). The estimated association was smaller and more variable comparing carbamazepine and oxcarbazepine to lamotrigine. In children, RDs were much smaller and more variable (5-year RD for initiation of oxcarbazepine vs lamotrigine, 0.29%; 95% CI, -0.12% to 0.69%; 5-year RD for initiation of valproate vs lamotrigine, 0.18%; 95% CI, -0.09% to 0.49%). Conclusions and Relevance: In this cohort study, valproate was associated with the highest risk of developing T2D in adults. The comparative safety was generally similar in children, but estimates were small and variable. In the absence of randomized trials, emulating target trials within health care databases can generate the age-specific drug safety data needed to inform treatment decision-making.

Cellular reprogramming with ATOH1, GFI1, and POU4F3 implicate epigenetic changes and cell-cell signaling as obstacles to hair cell regeneration in mature mammals.

Reprogramming of the cochlea with hair-cell-specific transcription factors such as ATOH1 has been proposed as a potential therapeutic strategy for hearing loss. ATOH1 expression in the developing cochlea can efficiently induce hair cell regeneration but the efficiency of hair cell reprogramming declines rapidly as the cochlea matures. We developed Cre-inducible mice to compare hair cell reprogramming with ATOH1 alone or in combination with two other hair cell transcription factors, GFI1 and POU4F3. In newborn mice, all transcription factor combinations tested produced large numbers of cells with the morphology of hair cells and rudimentary mechanotransduction properties. However, 1 week later, only a combination of ATOH1, GFI1 and POU4F3 could reprogram non-sensory cells of the cochlea to a hair cell fate, and these new cells were less mature than cells generated by reprogramming 1 week earlier. We used scRNA-seq and combined scRNA-seq and ATAC-seq to suggest at least two impediments to hair cell reprogramming in older animals. First, hair cell gene loci become less epigenetically accessible in non-sensory cells of the cochlea with increasing age. Second, signaling from hair cells to supporting cells, including Notch signaling, can prevent reprogramming of many supporting cells to hair cells, even with three hair cell transcription factors. Our results shed light on the molecular barriers that must be overcome to promote hair cell regeneration in the adult cochlea.

Bias reduction in conditional logistic regression.

We employ a general bias preventive approach developed by Firth (Biometrika 1993; 80:27-38) to reduce the bias of an estimator of the log-odds ratio parameter in a matched case-control study by solving a modified score equation. We also propose a method to calculate the standard error of the resultant estimator. A closed-form expression for the estimator of the log-odds ratio parameter is derived in the case of a dichotomous exposure variable. Finite sample properties of the estimator are investigated via a simulation study. Finally, we apply the method to analyze a matched case-control data from a low birthweight study.

Association of Selective Serotonin Reuptake Inhibitors With the Risk of Type 2 Diabetes in Children and Adolescents.

Importance: Concerns exist that use of selective serotonin reuptake inhibitors (SSRIs) increases the risk of developing type 2 diabetes (T2D) in adults, but evidence in children and adolescents is limited. In the absence of a randomized clinical trial, evidence must be generated using real-world data. Objective: To evaluate the safety of SSRI use in children and adolescents with respect to the associated risk of T2D. Design, Setting, and Participants: This cohort study of patients aged 10 to 19 years with a diagnosis for an SSRI treatment indication was conducted within the nationwide Medicaid Analytic eXtract (MAX; January 1, 2000, to December 31, 2014) and the IBM MarketScan (January 1, 2003, to September 30, 2015) databases. Data were analyzed from November 1, 2018, to December 6, 2019. Exposures: New users of an SSRI medication and comparator groups with no known metabolic adverse effects (no antidepressant exposure, bupropion hydrochloride exposure, or psychotherapy exposure). Within-class individual SSRI medications were compared with fluoxetine hydrochloride. Main Outcomes and Measures: Incident T2D during follow-up. Intention-to-treat effects were estimated using Cox proportional hazards regression models, adjusting for confounding through propensity score stratification. As-treated effects to account for continuous treatment were estimated using inverse probability weighting and marginal structural models. Results: A total of 1 582 914 patients were included in the analysis (58.3% female; mean [SD] age, 15.1 [2.3] years). The SSRI-treated group included 316 178 patients in the MAX database (publicly insured; mean [SD] age, 14.7 [2.1] years; 62.2% female) and 211 460 in the MarketScan database (privately insured; mean [SD] age, 15.8 [2.3] years; 63.9% female) with at least 2 SSRI prescriptions filled, followed up for a mean (SD) of 2.3 (2.0) and 2.2 (1.9) years, respectively. In publicly insured patients, initiation of SSRI treatment was associated with a 13% increased hazard of T2DM (intention-to-treat adjusted hazard ratio [aHR], 1.13; 95% CI, 1.04-1.22) compared with untreated patients. The association strengthened for continuous SSRI treatment (as-treated aHR, 1.33; 95% CI, 1.21-1.47), corresponding to 6.6 (95% CI, 4.2-10.4) additional cases of T2D per 10 000 patients treated for at least 2 years. Adjusted HRs were lower in privately insured patients (intention-to-treat aHR, 1.01 [95% CI, 0.84-1.23]; as-treated aHR, 1.10 [95% CI, 0.88-1.36]). Findings were similar when comparing SSRI treatment with psychotherapy (publicly insured as-treated aHR, 1.44 [95% CI, 1.25-1.65]; privately insured as-treated aHR, 1.21 [95% CI, 0.93-1.57]), whereas no increased risk was observed compared with bupropion treatment publicly insured as-treated aHR, 1.01 [95% CI, 0.79-1.29]; privately insured as-treated aHR, 0.87 [95% CI, 0.44-1.70]). For the within-class analysis, no medication had an increased hazard of T2D compared with fluoxetine. Conclusions and Relevance: These findings suggest that children and adolescents initiating SSRI treatment may be at a small increased risk of developing T2D, particularly publicly insured patients. The magnitude of association was more modest than previously reported, and the absolute risk was small. The potential small risk should be viewed in relation to the efficacy of SSRIs for its major indications in young patients.